Since the discovery of penicillin, pharmaceutical companies have produced more than one hundred antibacterial agents to combat a wide variety of bacterial infections. In the past several years, due to the misuse of these antibiotics there has been rapid emergence of bacterial resistance to several of these antibiotics. The multidrug resistance among these bacterial pathogens may also be due to mutation leading to more virulent clinical isolation, the most disturbing milestone has been the acquisition of resistance to vancomycin, an antibiotic generally regarded as the agent of last resort for serious Gram-positive infections. This growing multidrug resistance has recently rekindled interest in the search for a new structural class of antibiotics that inhibit or kill these bacteria possibly by novel mechanisms.
A problem of larger dimension is the increasing incidence of the more virulent, methicillin-resistant Staphylococcus aureas (MRSA) among clinical isolates found worldwide. As with vancomycin resistant organisms, many MRSA strains are resistant to most of the known antibiotics, but MRSA strains have remained sensitive to vancomycin. However, in view of the increasing reports of vancomycin resistant clinical isolates and growing problem of bacterial resistance, there is an urgent need for new molecular entities effective against the emerging and currently problematic Gram-positive organisms.
Recently, several oxazolidinones have been discovered, which inhibit protein synthesis by binding to the 50S-ribosomal subunit which is close to the site to which chloramphenicol and lincomycin bind but their mode of action is mechanistically distinct from these two antibiotics.
The new class of oxazolidinones of the present invention is useful for the treatment of a number of resistant and sensitive gram-positive strains both in vitro and in vivo. Some of the hitherto known compounds described in the prior art are outlined below:
(i) International Patent Application WO 93/23384 discloses compounds of formula (IIa)
where
Y represents a hydrogen atom, (C1–C6)alkyl or aryl, OH, O(C1–C6)alkyl, O-vinyl, O-phenyl, O—C(═O)(C1–C6)alkyl, —O—C(═O)-phenyl (phenyl can be substituted with one to three F, Cl, OCH3, OH, NH2, or (C1–C4)alkyl) or O—C(═O)—O—CH3, S—(C1–C6)alkyl, SO2—(C1–C6)alkyl, —SO2—N(R3)2, (where R3 is independently hydrogen, (C1–C4)alkyl or phenyl which can be substituted with one to three F, Cl, OCH3, OH, NH2, or (C1–C4)alkyl);
—C(═O)—(C1–C6)alkyl, —C(═O)—O—(C1–C6)alkyl, —C(═O)—N(R3)2, —C(═O)—CH(R4)N(R3)2, —C(═O)—CH(R4)—NH—C(NH)—NH2 (where R4 is an amino acid side chain); —N(R3)2, —N(CH2)m (where m is 2–6 and forms a cyclic structure with the nitrogen atom and where one or more carbon atoms can be replaced with S, O or NR3), —C(CH3)═N—OR or Y represents any of the groups given below:
where
R5 is OH, OCH3, CH2OH, CH2OCH3, CO2CH3, CO2C2H5, R6 represents CH3 or hydrogen, R7represents CH2 or C(═O), R8 represents hydrogen or ═O, p is 1 or 2, R9 represents O, S, S(O), SO2, CH2, NH, NCH3, NC2H5, NCHO, NCOCH3 or NCO2CH3, wherein each occurrence of said (C1–C6)alkyl may be substituted with one or more F, Cl, Br, I, OR1, COOR1, CN, SR1 or R1 (where R1 is a hydrogen or (C1–C4)alkyl); X and Z are independently (C1–C6) alkyl, (C3–C12)cycloalkyl or hydrogen or X and Z form a (C0–C3) bridging group, preferably X and Z are hydrogen;
U, V and W are independently (C1–C6)alkyl, F, Cl, Br, hydrogen or a (C1–C6)alkyl substituted with one or more of F, Cl, Br or I, preferably U and V are F and W is hydrogen;
R is hydrogen, (C1–C12)alkyl, (C3–C12)cycloalkyl, (C1–C6)alkoxy, (C1–C6)alkyl substituted with one or more F, Cl, Br, I or OH, n is 1 or 2; and q is 0–4 inclusive.
An example of this class of compounds is shown in formula (IIb)

(ii) International Patent Application WO 98/01447 discloses compounds of formula (IIc)
wherein
R1 represents —NHC(═O)Ra wherein Ra represents (C1–C4)alkyl;
R2 and R3 represent hydrogen or fluoro;
R4 and R5 are independently hydrogen or methyl;
R6 represent pyridyl, optionally substituted by substituents selected from (C1–C4)alkyl (optionally substituted), halo, trifluoromethyl, (C1–C4)alkyl-S(O)n— (wherein n is 0, 1 or 2), (C1–C4)alkyl SO2amino, (C1–C4)alkanoylamino, carboxy, hydroxy, amino, (C1–C4)alkylamino, di-(C1–C4)alkylamino, (C1–C4) alkoxycarbonyl, carbamoyl, N—(C1–C4)alkylcarbamoyl, di-(N—(C1–C4)alkyl) carbamoyl (wherein the (C1–C4)alkyl group on groups in the last two mentioned carbamoyl groups is optionally substituted by hydroxy, (C1–C4)alkoxy or (C1–C4) alkoxycarbonyl), (C2–C4)alkenyl (optionally substituted by carboxy or (C1–C4) alkoxycarbonyl), (C1–C4)alkoxy, cyano, or nitro groups.
An example of this class of compounds is shown in formula (IId)

(iii) International Patent Application No. WO 95/07271 discloses compounds of formula (IIe)
wherein
X represents O, S, SO, SO2, SNR10 or SONR10;
R represents hydrogen, (C1–C8)alkyl optionally substituted with one or more of the following: F, Cl, hydroxy, (C1–C8)alkoxy, (C1–C8)acyloxy or —OCH2Ph or R represents (C3–C6)cycloalkyl, amino, (C1–C8)alkylamino, (C1–C8) dialkylamino or (C1–C8)alkoxy;
R1 represents hydrogen except when X is O, then R1 can be hydrogen, CH3, cyano, —CO2H, CO2R or (CH2)mR11 (m is 1 or 2);
R2 represents independently hydrogen, F or Cl; R3 represents hydrogen or CH3;
R10 independently represents hydrogen, (C1–C4)alkyl (optionally substituted with chloro, fluoro, hydroxy, (C1–C8)alkoxy, amino, (C1–C8) alkylamino, or (C1–C8)dialkylamino) or p-toluenesulfonyl;
R11 represents hydrogen, hydroxy, OR, OCOR, NH2, NHCOR or N(R10)2; and n is 0, 1 or 2.
An example of this class of compounds is shown in formula (IIf)

(iv) International Patent Application WO 95/25106 discloses compounds of formula (IIg)
where
R is hydrogen atom, (C1–C8)alkyl, (C3–C6)cycloalkyl, amino, (C1–C8)alkylamino, (C1–C8)dialkylamino, (C1–C8)alkoxy or (C1–C8)halogen alkyl;
R1 and R3 are each and independently represents hydrogen atom, halogen atom, (C1–C8)alkyl, (C3–C6)cycloalkyl, —(CH2)m—OR11 or —C(═O)—R41;
X and Y are each and independently represents hydrogen atom, halogen atom;
R4 and R5 are each and independently represents hydrogen atom, (C1–C8)alkyl, (C1–C8)alkoxy, (C1–C8)alkylthio, —(CH2)m—OR51, —O—(CH2)m—OR51, —NR42R52, —N═CH—NR44R55, —C(═O)—NR42R52 or —(CH2)m—C(═A)—R41 or they may combine together to form ═O, ═NR43, ═S, ═CR44R54 or an optionally substituted, unsaturated or saturated 5 or 6 membered hetero ring having 1–3 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom;
R11 and R12 are each and independently represents hydrogen atom, (C1–C8)alkyl or methoxymethyl; R41 is hydrogen atom, —(CH2)m—OH, (C1–C8) alkyl, (C1–C8)alkoxy, —O—CH2—O—C(═O)—R11 or —(CH2)m—C(═O)—OR11;
R42 and R52 are each and independently represents hydrogen atom, —(CH2)m—OR11, (C1–C8)alkyl, —C(═O)—R41—C(═O)—NR11R12, —(CH2)p-phenyl, thiazol-2-yl or they may combine together to form a pyrrolidino group, a piperidino group, a piperazino group, a morpholino group or a thiomorpholino group, each of which may be substituted by (C1–C8)alkyl or —(CH2)m—OH;
R43 is hydrogen atom, —OR51, (C1–C8)alkyl, (C1–C8)alkoxy, —(CH2)p-phenyl, NR42R52, —NH—C(═NH)—NH2, [1,2,4]triazol-4-yl or cyano;
R44 and R55 are each and independently represents hydrogen atom, (C1–C8)alkyl, —C(═O)—R41 or —(CH2)p-phenyl;
R51 is hydrogen atom, (C1–C8)alkyl substituted by one or more hydroxy; (C2–C8)alkenyl, (C1–C8)halogenalkyl, —(CH2)m—OR11, —(CH2)m—C(═O)—R41, —C(═O)—(CH2)m—OR4 or tosyl; A is oxygen atom or ethyleneketal;
———is a double bond or a simple bond; m's are each and independently 0, 1 or 2; n is 0 or 1; p's are each and independently 1, 2, 3 or 4.
An example of this class of compounds is shown in formula (IIh)

(v) International Patent Application WO 96/13502 discloses compounds of formula (IIi)

Q is selected from the structures (a), (b), (c), (d) and (e);

R1 is H or F, OR7, SR7, NR8R9, CN, (C1–C4)alkoxycarbonyl, carboxamide, (C1–C4)acyl optionally substituted with one or more of the following: fluorine, hydroxy, (C1–C4)alkoxy, (C1–C4)acyloxy; NHO(C1–C6)alkyl or NHOCH2Ph, NSO2R where R is (C1–C6)alkyl optionally substituted with one or more F, Cl, (C1–C6)alkoxy or phenyl;
R2 is independently selected from hydrogen or fluorine, hydroxy, OR where R is (C1–C6)alkyl; (C1–C4)alkyl or Ph;
R3 is independently selected from H, phenyl, pyridyl or (C1–C3) alkyl which can be optionally substituted with F, Cl, hydroxy, (C1–C3) alkoxycarbonyl, (C1–C3)acyloxy, (C1–C3)alkoxy or N(C1–C4 alkyl)2;
R4 is independently H, OCH3, F or Cl; R5 is hydrogen, (C1–C8)alkyl optionally substituted with one or more of the following: F, Cl, hydroxy, (C1–C8) alkoxy, (C1–C8)acyloxy; (C3–C6)cycloalkyl, amino, (C1–C8)alkylamino, (C1–C8) dialkylamino, (C1–C8)alkoxy;
R6 is O, S, NR10, CR11R12, (OR)2, where R is (C1–C6)alkyl; O(CH2)mO, (SR)2 where R is (C1–C6)alkyl; S(CH2)mS;
R7 is H, (C1–C8)alkyl optionally substituted with one or more of the following: F, Cl, —CN, OH, (C1–C8)alkoxy, (C1–C8)acyloxy, (C1–C8) alkoxycarbonyl, phenyl; (C1–C8)acyl optionally substituted with one or more of the following: hydroxy, (C1–C8) alkoxy, (C1–C8)acyloxy; (C1–C8)alkoxycarbonyl, carboxamide optionally substituted with a (C1–C4)alkyl or phenyl on the carboxamide nitrogen; phenyl, optionally substituted with one or more of the following: halogen, CN, (C1–C3) alkoxy, (C1–C3)alkoxycarbonyl, (C1–C4)alkyl optionally substituted with one or more of F or (C1–C3) alkoxy;
R8 and R9 are independently selected from H, (C1–C8)alkyl optionally substituted with one or more of the following: F, Cl, —CN, OH, (C1–C8) alkoxy, (C1–C8)acyloxy, (C1–C8)alkoxycarbonyl, phenyl; (C1–C8)acyl optionally substituted with one or more of the following: hydroxy, (C1–C8)alkoxy, (C1–C8) acyloxy, amino, (C1–C4)acylamino, amino (C1–C4)acylamino; benzoyl optionally substituted with one or more of the following F, Cl, hydroxy, (C1–C8)alkoxy, (C1–C8)acyloxy, amino, (C1–C4)acylamino, (C1–C4) alkoxycarbonylamino; (C1–C8) alkoxycarbonyl, benzyloxycarbonyl, tertbutoxycarbonyl; carboxamide optionally substituted with a (C1–C4)alkyl or phenyl on the carboxamide nitrogen; trifluoracetyl, CO(C1–C6 alkyl);
R10 is H, OR7, NHR7, (C1–C8)alkyl optionally substituted with phenyl;
R11 and R12 are independently selected from H, F, (C1–C4)alkyl optionally substituted with halogen, hydroxy, (C1–C4)alkoxy, (C1–C4) alkoxycarbonyl, phenyl; (C1–C8)acyl, (C1–C4)alkoxycarbonyl, CN;
R17 is O or S; R18 and R19 are independently selected from H, (C1–C4)alkyl optionally substituted with halogen, hydroxy, (C1–C4)alkoxy; OH, (C1–C4)alkoxy optionally substituted with hydroxy or (C1–C4)alkoxy; NR8R9, —OC(O)(C1–C4)alkyl;
R20 is H, CH3; n is 0 or 1; m is 2 or 3.
An example of this class of compounds is shown in formula (IIj)

(vi) International Patent Application WO 97/27188 discloses compounds of formula (II k)

R1 is of the formula —NHC(═O)(C1–C4)alkyl, —NHS(O)n(C1–C4)alkyl, wherein n is 0, 1 or 2 or R1 is hydroxy;
R2 and R3 are independently hydrogen or fluoro;
R4 is hydrogen, methyl, ethyl or oxo;
R5 is hydrogen, (C1–C6)alkyl, (C2–C6)alkenyl, (C2–C6)alkynyl, or of the formula R6(CH2)m wherein m is 1–4 and R6 is trifluoromethyl, difluoromethyl, fluoromethyl, (C1–C4)alkoxy, (C1–C4)alkyl,S(O)p wherein p is 0, 1 or 2, (C1–C6) alkanoyloxy, di-(N—(C1–C4)alkyl)amino, N—((C1–C4)alkyl)(C1–C4)alkanoylamino, cyano, carboxy, (C1–C4)alkoxycarbonyl, carbamoyl, -di-(N—(C1–C4)alkyl) carbamoyl, N—((C1–C4)alkyl)(C1–C4)alkanesulphonamido, N1—((C1–C4)alkyl)-di(N3—(C1–C4)alkyl)ureido or of the formula —OC(═O)NR(R8) or N(R9)SO2NR7(R8) wherein R7 and R8 are independently hydrogen or (C1–C4)alkyl and R9 is (C1–C4) alkyl; or
m is 2–4 and R6 is hydroxy, (C1–C4)alkanoylamino, amino, (C1–C4) alkylamino, (C1–C4)alkanesulphonamido, ureido, di-(N3—(C1–C4)alkyl)ureido or of the formula NHSO2NR7(R8).
An example of this compound is shown in FIG. (IIl)

(vii) International Patent Application WO 98/01446 discloses compounds of formula (IIm)

R1 is of the formula —NHC(═O)Ra wherein Ra is (C1–C4)alkyl;
R2 and R3 are independently hydrogen or fluoro;
R4 and R5 are independently hydrogen or methyl;
R6 is a 6-membered heteroaryl ring containing 2 or 3 ring nitrogen atoms as the only ring heteroatoms and optionally substituted by substituents selected from (C1–C4)alkyl (optionally substituted), halo, trifluoromethyl, (C1–C4)alkylS(O)n— (wherein n is 0, 1 or 2), (C1–C4)alkylS(O)2 amino, (C1–C4) alkanoylamino, carboxy, hydroxy, amino, (C1–C4)alkylamino, di(C1–C4) alkylamino, (C1–C4)alkoxycarbonyl, carbamoyl, N—(C1–C4)alkylcarbamoyl, -di-(N—(C1–C4)alkyl)carbamoyl, (wherein (C1–C4)alkyl group or groups in the last two mentioned carbamoyl substituents is optionally substituted by hydroxy, (C1–C4) alkoxy or (C1–C4)alkoxycarbonyl), (C2–C4)alkenyl (optionally substituted by carboxy or (C1–C4)alkoxycarbonyl), (C1–C4)alkoxy, cyano or nitro.
An example of this compound is shown in FIG. (IIn)
